Ten patients consented for therapy; 2 patients screen-failed. Three patients completed therapy in Cohort 1, and five patients were treated in Cohort 2. One patient in Cohort 2 exited the trial for alternative therapy after one treatment cycle. The median number of cycles given was 15 (range 1-54). The mean of the maximum serum concentration (Cmax) of exemestane for Cohort 1 was 12.98 ng/mL and for Cohort 2 was 41.38 ng/mL. The AUCinffor the two cohorts was 51.73 and 184.17 ng x h/mL, respectively. The established maximum tolerated dose (MTD) was exemestane 50 mg PO daily with pemetrexed (500 mg/m2 IV q3 weeks) and carboplatin (AUC 6 mg x min/mL IV q3 weeks). No patients were removed from the study for adverse events. Clinical outcome, biomarker and QOL correlates are being collected.

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Conclusion

The combination of carboplatin, pemetrexed and exemestane in post-menopausal women with metastatic non-squamous, NSCLC is safe and well-tolerated. This data supports future clinical trials to establish efficacy with this combination therapy.

The randomized Phase III OAK trial investigated atezolizumab (anti–PD-L1) for treatment of advanced or metastatic previously-treated NSCLC. Atezolizumab significantly improved OS compared with docetaxel. Given that emerging studies have identified an association between metformin use and antitumor activity/immune interactions, we retrospectively explored metformin use in patients in the OAK study.

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Method

Patients received atezolizumab (1200 mg IV every 3 weeks [q3w]) until PD or loss of clinical benefit or docetaxel (75 mg/m2 IV q3w) until PD/unacceptable toxicity. Patients who received atezolizumab or docetaxel and did or did not receive metformin as concomitant therapy were retrospectively evaluated for ORR, PFS and OS (data cutoff, July 7, 2016). Unadjusted and adjusted comparisons between metformin users and non-metformin users were done.

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Result

Of the 425 patients randomized to atezolizumab, 36 received metformin; of the 425 patients randomized to docetaxel, 35 received metformin. Key baseline characteristics are shown in the table. Most metformin users started metformin before or within 30 days of study start (92% and 7% respectively). There was a numerical improvement in ORR in Atezo-Met patients compared with Atezo-NoMet patients (25% vs 13%; unadjusted P = 0.038 [adjusted = 0.093]), whereas there was no statistically significant improvement in ORR in Doc-Met patients compared with Doc-NoMet patients (17% vs 13%; unadjusted P = 0.499 [adjusted = 0.295]). There were no observable differences in PFS or OS in either the Atezo-Met vs Atezo-NoMet or Doc-Met vs Doc-NoMet groups (median PFS, 2.8 vs 2.8 mo and 4.2 vs 4.0 mo, respectively; median OS, 12.6 vs 14.1 mo and 9.1 vs 9.7 mo, respectively).

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Conclusion

Encouraging response rates suggest patients may benefit from receiving concomitant metformin treatment with atezolizumab. Lack of difference in PFS and OS may be due to lack of treatment effect or lack of statistical power and requires further prospective investigation.

Table. Characteristics of Patients Who Received Atezolizumab (Atezo) or Docetaxel (Doc) Combined With Metformin (Met) or No-Metformin (NoMet)

Atezo-Met, n (%) (n = 36)

Atezo-NoMet, n (%) (n = 389)

Doc-Met, n (%) (n = 35)

Doc-NoMet, n (%) (n = 390)

Diabetes mellitus type 2

33 (91.6)

28 (7.2)

33 (94.3)

26 (6.7)

Sex

Male

28 (77.8)

233 (59.9)

28 (80.0)

231 (59.2)

Female

8 (22.2)

156 (40.1)

7 (20.0)

159 (40.8)

Tobacco use history

Never smoker

2 (5.6)

82 (21.1)

2 (5.7)

70 (17.9)

Current/previous smoker

34 (94.4)

307 (78.9)

33 (94.3)

320 (82.1)

Histology

Nonsquamous

22 (61.1)

291 (74.8)

21 (60.0)

294 (75.4)

Squamous

14 (38.9)

98 (25.2)

14 (40.0)

96 (24.6)

No. of prior therapies

1

30 (83.3)

290 (74.6)

24 (68.6)

296 (75.9)

ECOG performance status at baseline

0

15 (41.7)

140 (36.0)

12 (34.3)

148 (37.9)

1

21 (58.3)

249 (64.0)

23 (65.7)

242 (62.1)

EGFR mutation status

Positive

1 (2.8)

41 (10.5)

1 (2.9)

42 (10.8)

PD-L1 IHC subgroup

TC3 or IC3 (PD-L1 ≥ 50% TC or 10% IC)

11 (30.6)

61 (15.7)

5 (14.3)

60 (15.4)

TC1/2/3 or IC1/2/3 (PD-L1 ≥ 1% on TC or IC)

27 (75.0)

214 (55.0)

19 (54.3)

203 (52.1)

TC0 and IC0 (PD-L1 < 1% on TC and IC)

9 (25.0)

171 (44.0)

16 (45.7)

183 (46.9)

TC, tumor cell; IC, tumor-infiltrating immune cell.

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